Four-Hydroxyphenylpyruvic Acid Oxidase Deficiency with Normal Fumarylacetoacetase: a New Variant Form of Hereditary Hypertyrosinemia

Endo, Fumio; Kitano, Akihiko; Uehara, Itsuko; Nagata, Noriyuki; Matsuda, Ichiro; Shinka, Toshikatsu; Kuhara, Tomiko; Matsumoto, Isamu

doi:10.1203/00006450-198302000-00002

Cited by 55 publications

(35 citation statements)

References 16 publications

(20 reference statements)

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“…HGA production in plants is critical for the production of plastoquinone and tocopherols, essential quinine compounds, and growth of 4HPPD mutant lines can be rescued either by expression of 4HPPD or by application of exogenous HGA (29,30). In humans, the role of 4HPPD can be more directly correlated to tyrosine degradation, since humans deficient in 4HPPD function are at risk for tyrosinemia type III, a disorder caused by the accumulation of tyrosine and phenolic metabolites that leads to mental retardation or neurological symptoms (12).…”

Section: Discussionmentioning

confidence: 99%

Isolation of Antibiotics Turbomycin A and B from a Metagenomic Library of Soil Microbial DNA

Gillespie

Brady

Bettermann

et al. 2002

Appl Environ Microbiol

424

244

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Three clones, P57G4, P89C8, and P214D2, produced colonies with a dark brown melanin-like color. We fractionated the culture supernatant of P57G4 to identify the pigmented compound or compounds. Methanol extracts of the acid precipitate from the culture supernatant contained a red and an orange pigment. Structural analysis revealed that these were triaryl cations, designated turbomycin A and turbomycin B, respectively; both exhibited broad-spectrum antibiotic activity against gram-negative and gram-positive organisms. Mutagenesis, subcloning, and sequence analysis of the 25-kb insert in P57G4 demonstrated that a single open reading frame was necessary and sufficient to confer production of the brown, orange, and red pigments on E. coli; the predicted product of this sequence shares extensive sequence similarity with members of the 4-hydroxyphenylpyruvate dioxygenase (4HPPD) family of enzymes. Another member of the same family of genes, lly, which is required for production of the hemolytic pigment in Legionella pneumophila, also conferred production of turbomycin A and B on E. coli. We further demonstrated that turbomycin A and turbomycin B are produced from the interaction of indole, normally secreted by E. coli, with homogentisic acid synthesized by the 4HPPD gene products. The results demonstrate successful heterologous expression of DNA extracted directly from soil as a means to access previously uncharacterized small organic compounds, serving as an example of a chimeric pathway for the generation of novel chemical structures.

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Section: Discussionmentioning

confidence: 99%

Isolation of Antibiotics Turbomycin A and B from a Metagenomic Library of Soil Microbial DNA

Gillespie

Brady

Bettermann

et al. 2002

Appl Environ Microbiol

424

244

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“…is from mouse strain III (Hpd Ϫ/Ϫ ) (13-15), a model for human hereditary tyrosinemia type 3 (27) that is characterized by elevation of blood tyrosine and the absence of visceral injuries (13,27). There is a C to T transition at nucleotide ϩ7 on exon 7 of the Hpd gene on chromosome 5 of the III mouse, the result being premature termination of translation (15).…”

Section: Phenotype Of the Double Mutants (Fahmentioning

confidence: 99%

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

Endo¹,

Kubo²,

Awata³

et al. 1997

Journal of Biological Chemistry

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Hereditary tyrosinemia 1 (HT1) is characterized by progressive liver damage, from infancy, and by a high risk for hepatocellular carcinoma. HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. Lethal albino deletion c 14CoS mice and mice with target-disrupted Fah are models for HT1, but they die in the perinatal period, albeit with a different phenotype from that seen in HT1 in humans. We first asked whether homozygous null mutation of the 4-hydroxyphenylpyruvate dioxygenase gene Hpd could rescue the homozygous c 14CoS mice (c 14CoS /c 14CoS or Fah ؊/؊ ). The double mutant Fah ؊/؊ Hpd ؊/؊ mice appeared normal, at least until age 18 months, and there was no evidence of liver disease, findings that facilitated examination of the effect of Fah ؊/؊ on mature and unmodified hepatocytes in vivo. The hepatocytes of Fah ؊/؊ undergo rapid apoptosis, and acute death follows. Essentially the same phenomena were observed when Fah ؊/؊ Hpd ؊/؊ mice were administered homogentisate intraperitoneally. These changes in liver pathology in Fah ؊/؊ Hpd ؊/؊ mice after the administration of homogentisate were associated with massive urinary excretion of succinylacetone. These results suggest that accumulation of fumarylacetoacetate, maleylacetoacetate, or succinylacetone seems to trigger the endogenous process of apoptosis in hepatocytes that lack fumarylacetoacetate hydrolase activity. This apoptosis may be related to the development of hepatocellular carcinomas seen in HT1 patients and pharmaceutically treated fumarylacetoacetate hydrolase-deficient mice.

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“…Mutations in the HPD locus are related to two known distinct diseases, hereditary tyrosinemia type 3 and hawkinsinuria, and HPD activity is markedly reduced in the liver of patients with HT1 (2). HT3 is characterized by elevated blood concentrations of Tyr and massive urinary excretion of 4-hydroxyphenylpyruvic acid (4-HPP), 4-hydroxyphenyllactic acid, and hydrophenylacetic acid (3). Clinical symptoms in some patients include mild mental retardation, ataxia, and convulsions, and these symptoms are likely due to the elevation of 4-HPP and Tyr in body fluids.…”

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confidence: 99%

“…Interestingly, the deletion strain was also unable to grow on mixtures of a derepressing concentration of lactose and Phe as single carbon sources, VOL. 5, 20065, NOTE 1443 suggesting that, analogous to the situation in humans (3,18), the absence of hpdA directs the possible accumulation of 4-HPP and Tyr as toxic metabolites. Type 3 tyrosinemia is characterized by elevated blood concentrations of Tyr and massive urinary excretion of 4-HPP, 4-hydroxyphenyllactic, and 4-hydroxyphenylacetic acid (2,3,18).…”

mentioning

confidence: 99%

“…5, 20065, NOTE 1443 suggesting that, analogous to the situation in humans (3,18), the absence of hpdA directs the possible accumulation of 4-HPP and Tyr as toxic metabolites. Type 3 tyrosinemia is characterized by elevated blood concentrations of Tyr and massive urinary excretion of 4-HPP, 4-hydroxyphenyllactic, and 4-hydroxyphenylacetic acid (2,3,18). Taking into consideration that the growth of A. nidulans ⌬hpdA strain was inhibited in MCϩPheϩLac medium, this opened the possibility that 4-HPP and/or 4-HPP metabolites were accumulating as a result of the metabolic block caused by the hpdA deletion.…”

mentioning

confidence: 99%

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Fungal Metabolic Model for Tyrosinemia Type 3: Molecular Characterization of a Gene Encoding a 4-Hydroxy-Phenyl Pyruvate Dioxygenase from Aspergillus nidulans

et al. 2006

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Four-Hydroxyphenylpyruvic Acid Oxidase Deficiency with Normal Fumarylacetoacetase: a New Variant Form of Hereditary Hypertyrosinemia

Cited by 55 publications

References 16 publications

Isolation of Antibiotics Turbomycin A and B from a Metagenomic Library of Soil Microbial DNA

Isolation of Antibiotics Turbomycin A and B from a Metagenomic Library of Soil Microbial DNA

Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval of the Tyrosine Catabolic Pathway

Fungal Metabolic Model for Tyrosinemia Type 3: Molecular Characterization of a Gene Encoding a 4-Hydroxy-Phenyl Pyruvate Dioxygenase from Aspergillus nidulans

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